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Background Heart failure (HF) is a serious and advanced stage of various cardiac diseases with high mortality and rehospitalization rates. Phosphoglycerate mutase 2 (PGAM2) overexpression was identified in the serum of patients with HF. Material/methods One hundred and fifty-three cases of HF were included in the present work. According to New York Heart Association (NYHA) classification, 22 were grade II, 84 were grade III, and 47 were grade IV. Serum PGAM2, NT-proBNP, B-type natriuretic peptide (BNP), troponin T (TNT), and Cys-C of HF patients were detected using ELISA assay. Left ventricular ejection fraction, left ventricular end-diastolic inner diameter, and left atrium (LA) inner diameter of the included cases were also detected by the cardiac color Doppler. Results The number of patients with atrial fibrillation was significantly higher in NYHA IV group than in groups II and III with statistical difference (p < 0.05). The serum PGAM2, NT-proBNP, and Cys-C were significantly higher in NYHA IV group than in NYHA II and NYHA III groups (p all < 0.05). NT-proBNP had the highest prediction efficacy of HF severity and PGAM2 was also a potential biomarker for HF severity evaluation with relatively high sensitivity, specificity, and area under the ROC. The overall survival among NYHA II, III, and IV groups were statistically different (p = 0.04) with the median survival time of 25 months for NYHA III and IV groups. Conclusion PGAM2 is a new promising biomarker for evaluation of the severity of HF. Combination detection using multiple serum factors such as PGAM2, NT-proBNP, BNP, TNT, and Cys-C can improve the HF severity differential diagnosis performance.